WO2011016861A2 - Nouvelles protéines régulatrices et nouveaux inhibiteurs - Google Patents

Nouvelles protéines régulatrices et nouveaux inhibiteurs Download PDF

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Publication number
WO2011016861A2
WO2011016861A2 PCT/US2010/002173 US2010002173W WO2011016861A2 WO 2011016861 A2 WO2011016861 A2 WO 2011016861A2 US 2010002173 W US2010002173 W US 2010002173W WO 2011016861 A2 WO2011016861 A2 WO 2011016861A2
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Prior art keywords
gsap
imatinib
peptide
secretase
disease
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PCT/US2010/002173
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English (en)
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WO2011016861A3 (fr
Inventor
Paul Greengard
Wenjie Lou
Gen He
Peng Li
Lawrence Wennogle
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Intra-Cellular Therapies, Inc.
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Priority to EP10806753.9A priority Critical patent/EP2461673A4/fr
Priority to SG2012008215A priority patent/SG178279A1/en
Priority to JP2012523606A priority patent/JP6166534B2/ja
Publication of WO2011016861A2 publication Critical patent/WO2011016861A2/fr
Priority to US13/367,049 priority patent/US9605041B2/en
Publication of WO2011016861A3 publication Critical patent/WO2011016861A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C07K14/4705—Regulators; Modulating activity stimulating, promoting or activating activity
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
    • A01K67/027—New breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0007—Nervous system antigens; Prions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6827—Hybridisation assays for detection of mutation or polymorphism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/686—Polymerase chain reaction [PCR]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
    • A01K2207/05—Animals modified by non-integrating nucleic acids, e.g. antisense, RNAi, morpholino, episomal vector, for non-therapeutic purpose
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A01K2217/054—Animals comprising random inserted nucleic acids (transgenic) inducing loss of function
    • A01K2217/058—Animals comprising random inserted nucleic acids (transgenic) inducing loss of function due to expression of inhibitory nucleic acid, e.g. siRNA, antisense
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/15—Animals comprising multiple alterations of the genome, by transgenesis or homologous recombination, e.g. obtained by cross-breeding
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/20—Animal model comprising regulated expression system
    • A01K2217/203—Animal model comprising inducible/conditional expression system, e.g. hormones, tet
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases
    • A01K2267/0312—Animal model for Alzheimer's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer

Definitions

  • the A ⁇ 40 form is not associated with early deposits of amyloid plaques.
  • the A ⁇ 42 form accumulates early and predominantly in the parenchymal plaques and there is strong evidence that A ⁇ 42 plays a major role in amyloid plaque deposits in familial Alzheimer's disease patients.
  • Neurofibrillary tangles consist of aggregated tau protein and their role in AD pathology is less clear.
  • AD symptoms are most closely correlated with total brain A ⁇ rather than plaques.
  • About 10% of AD cases result from autosomal dominant inheritance of mutations in either the APP or the presenilin 1 and presenilin 2 genes. In both cases, increased production of total A ⁇ or A ⁇ 42 versus A ⁇ 40 results.
  • APP-CTF is the truncated form of APP- ⁇ -CTF spanning from its N-terminus to HHGV 64 .
  • APP-CTF-T2 is the truncated form of APP- ⁇ -CTF spanning from its N- terminus to VMLKK 55 . Truncated forms are overexpressed in HEK293 cells and
  • gSAP In contrast to some other regulators of ⁇ -secretase activity, gSAP is selective and influences cleavage of APP but not of Notch. Although the mechanism of substrate selection by ⁇ -secretase remains unclear, a number of other proteases and phosphatases with broad substrate recognition can achieve specificity through auxiliary factors that couple the core enzyme to a subset of substrates. To determine the mechanism by which gSAP might confer such specificity, we analyze its binding to specific substrates in HEK293 cells. gSAP- 16K immunoprecipitates with APP-CTF but not with Notch ⁇ E.
  • the invention provides
  • gSAP monoclonal antibodies to gSAP, e.g., capable of inhibiting its interaction with gamma-secretase and so inhibiting or reducing as A ⁇ production and accumulation;
  • the invention additionally provides a method of identifying persons at risk of developing AD comprising checking for elevated expression levels and/or mutations in gSAP relative to normal values as identified using a control population.
  • a method for producing an inhibitory effect against the accumulation of abnormal protein aggregates in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present invention provides methods of treatment of
  • RNA molecules e.g. recombinant adeno-associated virus 2 (AA V2) carrying gSAP shRNA;
  • DIPEA iV,iV-Diisopropylethylamine
  • membrane pellets are prepared as described above and resuspended in 50 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl 2 , 5 mM CaCl 2 .
  • human embryonic kidney cells (HEK293) grown to -80% confluency ( ⁇ 10 7 cells) are incubated with 0.1 ⁇ M 3 H-GOl in Opti-MEM for 2 hours in an incubator at 37 0 C, with 5% CO 2 before being transferred to ice for an additional hour. Medium is removed and cells are washed twice with cold phosphate buffered saline (PBS), pH 7.4. Photolysis is conducted on ice for 2 min using a compact UV lamp (4 watt, model UVGL-25, UVP Inc.) at 254 nM. As controls, cells are incubated either without UV crosslinking or in the presence of 50 ⁇ M unlabeled imatinib.
  • PBS cold phosphate buffered saline
  • Example 8 In vitro ⁇ -secretase assay.
  • Immunoprecipitation of APP-CTF, but not of Notch ⁇ E, is associated with co- immunoprecipitation of gSAP-16K. Treatment with imatinib reduces the association between gSAP-16K and APP-CTF.
  • TGCTGTTGACAGTGAGCGCGGGTATAGCCTTATTTGCATATAGTGAAGCCACAGA TGTATATGCAAATAAGGCTATACCCATGCCTACTGCCTCGGA ) ispurchased from Openbiosystems/Thermo Scientific.
  • the hairpin region is excised and inserted into AA V2- siln4.1 -MCS-EGFP vector (Vector biolabs) via BamHI and HindIII sites.
  • the triple transgenic AD mice (6 months old) are analyzed for A ⁇ .
  • the double transgenic AD mice (13 months old) are analyzed for plaques.
  • the membrane is pelleted down, solubilized in 50 mM Hepes, 150 mM NaCl, 1% octyl ⁇ -D-glucopyranoside, and bound to Myone streptavidin Tl beads for 1 hr, then washed 3 times.
  • the captured protein is released by incubation with SDS sample buffer and detected by western blot.

Abstract

L'invention porte sur une protéine jusqu'à présent non caractérisée (protéine d'activation de gamma-secrétase ou gSAP) qui active la γ-secrétase pour produire une protéine β-amyloïde (Aβ). Le dépôt d'Aβ a été associé à la maladie d'Alzheimer et à d'autres pathologies. Ainsi, l'invention porte, de plus, par exemple, sur des procédés de criblage et de nouveaux outils de recherche, sur des inhibiteurs de cette nouvelle protéine et sur des procédés de diagnostic, de traitement et de lutte contre la maladie d'Alzheimer et autres états neurodégénératifs associés au dépôt d'Aβ.
PCT/US2010/002173 2009-08-05 2010-08-05 Nouvelles protéines régulatrices et nouveaux inhibiteurs WO2011016861A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP10806753.9A EP2461673A4 (fr) 2009-08-05 2010-08-05 Nouvelles protéines régulatrices et nouveaux inhibiteurs
SG2012008215A SG178279A1 (en) 2009-08-05 2010-08-05 Novel regulatory proteins and inhibitors
JP2012523606A JP6166534B2 (ja) 2009-08-05 2010-08-05 新規調節タンパク質および阻害剤
US13/367,049 US9605041B2 (en) 2009-08-05 2012-02-06 Regulatory proteins and inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US23146209P 2009-08-05 2009-08-05
US61/231,462 2009-08-05

Related Child Applications (1)

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US13/367,049 Continuation US9605041B2 (en) 2009-08-05 2012-02-06 Regulatory proteins and inhibitors

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WO2011016861A2 true WO2011016861A2 (fr) 2011-02-10
WO2011016861A3 WO2011016861A3 (fr) 2012-08-23

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US (1) US9605041B2 (fr)
EP (1) EP2461673A4 (fr)
JP (2) JP6166534B2 (fr)
SG (2) SG178279A1 (fr)
WO (1) WO2011016861A2 (fr)

Cited By (8)

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Publication number Priority date Publication date Assignee Title
WO2013067157A1 (fr) * 2011-11-01 2013-05-10 Modgene, Llc Compositions et méthodes de réduction de la charge amyloïde-bêta
WO2013163423A1 (fr) * 2012-04-25 2013-10-31 Musc Foundation For Research Development Compositions et procédés pour la guérison des plaies et la réparation tissulaire
US9801882B2 (en) 2013-02-17 2017-10-31 Intra-Cellular Therapies, Inc. Phosphodiesterase-1 inhibitors and their use in treatment of cardiovascular diseases
US10131671B2 (en) 2014-08-07 2018-11-20 Intra-Cellular Therapies, Inc. Organic compounds
US10238660B2 (en) 2009-05-13 2019-03-26 Intra-Cellular Therapies, Inc. Organic compounds
US10285992B2 (en) 2014-08-07 2019-05-14 Intra-Cellular Therapies, Inc. Combinations of PDE1 inhibitors and NEP inhibitors and associated methods
US10682354B2 (en) 2016-03-28 2020-06-16 Intra-Cellular Therapies, Inc. Compositions and methods
US11759465B2 (en) 2018-01-31 2023-09-19 Intra-Cellular Therapies, Inc. Uses

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KR102234112B1 (ko) * 2014-06-27 2021-04-02 한양대학교 산학협력단 뇌 특이적 핵산 전달
JP6994715B2 (ja) * 2017-10-04 2022-02-04 国立大学法人京都大学 Ｂｃｒ－Ａｂｌタンパク質イメージング用分子プローブ

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US20130149309A1 (en) 2013-06-13
JP2013500741A (ja) 2013-01-10
EP2461673A2 (fr) 2012-06-13
SG10201507362TA (en) 2015-10-29
WO2011016861A3 (fr) 2012-08-23
JP6166534B2 (ja) 2017-07-19
US9605041B2 (en) 2017-03-28
JP2016102110A (ja) 2016-06-02
SG178279A1 (en) 2012-03-29

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